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Silver and platinum nanoparticles synergy

ABSTRACT: In this study, we compared the effects of silver and platinum NPs on the main components of the blood brain barrier model: human cerebral microvascular endothelial cells (hCMEM/D3) and human primary astrocytes under single and co-exposure NP conditions. The co-exposure to two types of NPs synergistically inhibited proliferation of both cell types with the greater extent observed for endothelial cells (the combination index (CI) values for all tested concentrations were below 0.2 corresponding to strong or extreme synergism). In addition, NP-induced toxicity demonstrated dependence on the cell type with astrocytes being more tolerant to the metal NPs. The mechanism of synergy was further explored with short-time incubation time points (up to 30 min), where the cell metabolic activity was decreased to approximately 60% of the controls. The data obtained from the proteomics analysis suggests immunosuppression and deregulation of the extracellular matrix organization as well as contribution of the p75NTR-associated cell death executor (NADE)-dependent apoptotic mechanism in the synergistic cytotoxicity of NPs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Cerebral Cortex Endothelial Cell, Astrocyte, Blood

SUBMITTER: Vladimir Gorshkov

LAB HEAD: Frank Kjeldsen

PROVIDER: PXD014425 | Pride | 2022-11-08

REPOSITORIES: Pride

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Project description:Poly-ethylene-glycol (PEG)-based nanoparticles (NPs) - including cylindrical micelles (CNPs), spherical micelles (SNPs), and PEGylated liposomes (PLs) - are hypothesized to be cleared in vivo by opsonization followed by liver macrophage phagocytosis. This hypothesis has been used to explain the rapid and significant localization of NPs to the liver after administration into the mammalian vasculature. Here, we show that the opsonization-phagocytosis nexus is not the major factor driving PEG-NP – macrophage interactions. First, mouse and human blood proteins had insignificant affinity for PEG-NPs. Second, PEG-NPs bound macrophages in the absence of serum proteins. Third, lipoproteins blocked PEG-NP binding to macrophages. Because of these findings, we tested the postulate that PEG-NPs bind (apo)lipoprotein receptors. Indeed, PEG-NPs triggered an in vitro macrophage transcription program that was similar to that triggered by lipoproteins and different from that triggered by lipopolysaccharide (LPS) and group A Streptococcus. Unlike LPS and pathogens, PLs did not increase transcripts involved in phagocytosis or inflammation. High-density lipoprotein (HDL) and SNPs triggered remarkably similar mouse bone-marrow-derived macrophage transcription programs. Unlike opsonized pathogens, CNPs, SNPs, and PLs lowered macrophage autophagosome levels and either reduced or did not increase the secretion of key macrophage pro-inflammatory cytokines and chemokines. Thus, the sequential opsonization and phagocytosis process is likely a minor aspect of PEG-NP – macrophage interactions. Instead, PEG-NP interactions with (apo)lipoprotein and scavenger receptors appear to be a strong driving force for PEG-NP – macrophage binding, entry, and downstream effects. We hypothesize that the high presence of these receptors on liver macrophages and on liver sinusoidal endothelial cells is the reason PEG-NPs localize rapidly and strongly to the liver. To investigate the response of macrophages to nanoparticles, we incubated PEGylated liposomes (PLs), spherical nanoparticles (SNPs), high-density lipoproteins (HDL), low-density lipoproteins (LDL), Group A Streptococcus pathogens (JRS4), and lipopolysaccharide (LPS) with RAW264.7 and primary bone-marrow derived mouse macrophages

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Silver and platinum nanoparticles synergy

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